A novel splicing mutation in 5'UTR of GJB1 causes X‐linked Charcot—Marie–tooth disease
Abstract Background Charcot–Marie–Tooth (CMT) disease is the most frequent hereditary motor sensory neurological disease. GJB1 gene is the second most frequent cause of CMT, accounting for approximately 10% of CMT cases worldwide. We identified a large Han family with X‐linked CMT disease. Methods I...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-03-01
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| Series: | Molecular Genetics & Genomic Medicine |
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| Online Access: | https://doi.org/10.1002/mgg3.2108 |
| _version_ | 1797871862467788800 |
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| author | MeiYi Li Minna Yin Li Yang Zhiheng Chen Peng Du Ling Sun Juan Chen |
| author_facet | MeiYi Li Minna Yin Li Yang Zhiheng Chen Peng Du Ling Sun Juan Chen |
| author_sort | MeiYi Li |
| collection | DOAJ |
| description | Abstract Background Charcot–Marie–Tooth (CMT) disease is the most frequent hereditary motor sensory neurological disease. GJB1 gene is the second most frequent cause of CMT, accounting for approximately 10% of CMT cases worldwide. We identified a large Han family with X‐linked CMT disease. Methods In this study, the probands and his mother underwent electrophysiological examinations and other family members were assessed retrospectively. Whole‐exome sequencing, Sanger sequencing, and SNP array linkage analysis were performed to find and confirm the variant. The functional effect of the identified variant was further investigated in HEK293 cells and MCF‐7 cells by minigene splicing assay. Results The affected individuals had some clinical symptoms including symmetric atrophy and progressive weakness of the distal muscles in their twenties. Electrophysiological examinations result in peripheral nerve injury of the upper and lower limbs. Whole‐exome sequencing identified a novel hemizygous deletion mutation (NM_000166: c.‐16‐8_‐14del) in the GJB1 gene. SNP array linkage analysis and co‐segregation analysis confirmed this mutation. Minigene splicing assay verified that this mutation leads to the activation of cryptic splicing sites in exon 2 which results in the deletion of exon 2. Conclusion Our study provides theoretical guidance for prenatal diagnosis and subsequent fertility of this family. This result expands the spectrum of mutations in GJB1 known to be associated with CMTX and contributes to the diagnosis of CMT and clinical genetic counseling. |
| first_indexed | 2024-04-10T00:49:45Z |
| format | Article |
| id | doaj.art-7211409d62824e54834b7f058efbaa4e |
| institution | Directory Open Access Journal |
| issn | 2324-9269 |
| language | English |
| last_indexed | 2024-04-10T00:49:45Z |
| publishDate | 2023-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Genetics & Genomic Medicine |
| spelling | doaj.art-7211409d62824e54834b7f058efbaa4e2023-03-13T12:14:56ZengWileyMolecular Genetics & Genomic Medicine2324-92692023-03-01113n/an/a10.1002/mgg3.2108A novel splicing mutation in 5'UTR of GJB1 causes X‐linked Charcot—Marie–tooth diseaseMeiYi Li0Minna Yin1Li Yang2Zhiheng Chen3Peng Du4Ling Sun5Juan Chen6Center of Reproductive Medicine, Guangzhou Women and Children's Medical Center Guangzhou Medical University Guangzhou ChinaCenter of Reproductive Medicine, Guangzhou Women and Children's Medical Center Guangzhou Medical University Guangzhou ChinaCenter of Reproductive Medicine, Guangzhou Women and Children's Medical Center Guangzhou Medical University Guangzhou ChinaCenter of Reproductive Medicine, Guangzhou Women and Children's Medical Center Guangzhou Medical University Guangzhou ChinaGenetic Testing Center, Guangzhou Women and Children's Medical Center Guangzhou Medical University Guangzhou ChinaCenter of Reproductive Medicine, Guangzhou Women and Children's Medical Center Guangzhou Medical University Guangzhou ChinaCenter of Reproductive Medicine, Guangzhou Women and Children's Medical Center Guangzhou Medical University Guangzhou ChinaAbstract Background Charcot–Marie–Tooth (CMT) disease is the most frequent hereditary motor sensory neurological disease. GJB1 gene is the second most frequent cause of CMT, accounting for approximately 10% of CMT cases worldwide. We identified a large Han family with X‐linked CMT disease. Methods In this study, the probands and his mother underwent electrophysiological examinations and other family members were assessed retrospectively. Whole‐exome sequencing, Sanger sequencing, and SNP array linkage analysis were performed to find and confirm the variant. The functional effect of the identified variant was further investigated in HEK293 cells and MCF‐7 cells by minigene splicing assay. Results The affected individuals had some clinical symptoms including symmetric atrophy and progressive weakness of the distal muscles in their twenties. Electrophysiological examinations result in peripheral nerve injury of the upper and lower limbs. Whole‐exome sequencing identified a novel hemizygous deletion mutation (NM_000166: c.‐16‐8_‐14del) in the GJB1 gene. SNP array linkage analysis and co‐segregation analysis confirmed this mutation. Minigene splicing assay verified that this mutation leads to the activation of cryptic splicing sites in exon 2 which results in the deletion of exon 2. Conclusion Our study provides theoretical guidance for prenatal diagnosis and subsequent fertility of this family. This result expands the spectrum of mutations in GJB1 known to be associated with CMTX and contributes to the diagnosis of CMT and clinical genetic counseling.https://doi.org/10.1002/mgg3.2108Charcot–Marie–tooth diseasegenetic counselingGJB1novel mutation |
| spellingShingle | MeiYi Li Minna Yin Li Yang Zhiheng Chen Peng Du Ling Sun Juan Chen A novel splicing mutation in 5'UTR of GJB1 causes X‐linked Charcot—Marie–tooth disease Molecular Genetics & Genomic Medicine Charcot–Marie–tooth disease genetic counseling GJB1 novel mutation |
| title | A novel splicing mutation in 5'UTR of GJB1 causes X‐linked Charcot—Marie–tooth disease |
| title_full | A novel splicing mutation in 5'UTR of GJB1 causes X‐linked Charcot—Marie–tooth disease |
| title_fullStr | A novel splicing mutation in 5'UTR of GJB1 causes X‐linked Charcot—Marie–tooth disease |
| title_full_unstemmed | A novel splicing mutation in 5'UTR of GJB1 causes X‐linked Charcot—Marie–tooth disease |
| title_short | A novel splicing mutation in 5'UTR of GJB1 causes X‐linked Charcot—Marie–tooth disease |
| title_sort | novel splicing mutation in 5 utr of gjb1 causes x linked charcot marie tooth disease |
| topic | Charcot–Marie–tooth disease genetic counseling GJB1 novel mutation |
| url | https://doi.org/10.1002/mgg3.2108 |
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